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Penn Students Searching for Treatment for Parkinsonís

- Aug 01 2013

By Madeleine Kruhly

Awarded summer fellowships by the Parkinson's Disease Foundation, University of Pennsylvania students Solongo Batjargal and Eric Lin look to play instrumental roles in the development of a treatment for Parkinson's.

Fellows are funded for 10 weeks of clinical or lab work and are supervised by an expert in the field.

Although leading separate projects, Batjargal and Lin focus on the alpha-synucleinprotein, found primarily in neural tissue. In Parkinson's patients, alpha-synuclein forms Lewy bodies, abnormal aggregates of proteins inside nerve cells.

A fourth-year doctoral student in chemistry, Batjargal works under the direction of E. James Petersson, assistant professor of chemistry.

"We're interested in developing tools for understanding how proteins move and change shape," Petersson says. "We started to work with alpha-synuclein in 2011, and now we have an appreciation for how little was understood about the protein."

Alpha-synucleins are dynamic molecules involved in signaling between nerve cells, but Batjargal notes that, when the proteins change shape and clump together, serious complications can occur.

"When the protein is misfolded, it is not able to carry out its functions," Batjargal says. "We don't know why this process happens, so we want to form a detailed picture of the misfolding on a molecular resolution."

In order to understand these patterns, Batjargal examines the conformations of the alpha-synuclein. She uses fluorescence resonance energy transfer, or FRET, as a tool to track the movements of the proteins and observe the changes in the highly organized configurations adopted in the process of misfolding.

"If we understand how the alpha-synuclein protein changes shape, then a drug could possibly be designed to block the initiation of misfolding," Batjargal says.

It's this step, that of blocking the faulty beta-sheet conformation, that could possibly deter cell death and eventual motor disability, a hallmark of Parkinson's disease.

"We're not a drug discovery lab," Petersson says, "but we hope our research will contribute to the development of possible medications that would target the toxic shapes of the proteins and leave the normal form alone."

Petersson notes that integral to this research is his partnership with the Center for Neurodegenerative Disease Research, where fellow recipient Eric Lin works with Virginia M.-Y. Lee, director of the center, and John Q. Trojanowski, co-director.

Eric Lin is in his second year at Penn's Perelman School of Medicine. He became interested in neurodegenerative diseases while volunteering in high school for a music therapy program.

Like Batjargal, Lin investigates the properties of the alpha-synuclein, but his mentor Lee explains that there are different strains of the protein, each associated with a particular type of pathology.

"We realized there was something quite strange about Parkinson's," Lee says. "Some patients can have Parkinson's and only experience a movement disorder. Others can live for a long time with the disease and then develop dementia."

These differences in pathology pointed to the presence of multiple alpha-synuclein strains and thus multiple conformations. From this conclusion, Lee and her team generated antibodies that would be able to recognize one strain and one shape.

For his project, Lin focuses on a new antibody matched to the alpha-synuclein strain that causes aggregates of tau, a protein often associated with Alzheimer's pathology.

"We are seeing whether we can find any patterns in terms of where that strain is present in different alpha-synucleinopathies, such as Parkinson's," Lin says.

Lin says that reclassifications of the disease by individual alpha-synuclein strain could lead to new diagnostic tools and more targeted therapeutic approaches.

"There's currently a one-size-fits-all treatment for Parkinson's," Lin says. "Our idea is that, if we find patterns of strain pathology associated with Parkinson's, we could use a targeted strain-selective antibody to slow down the progression of the disease."

Lee emphasizes that these antibodies are extremely useful tools, with a two-fold purpose.

"Antibodies could not only eventually be used to treat Parkinson's patients through immunotherapy but to also develop biomarkers for early diagnoses of the disease," she says.

"Doing research on neurodegenerative diseases is something that I had been looking forward to for long time," Lin says. "It was something that really hadn't been fulfilled until this point."